The possibility that B cell-macrophage interactions are genetically restricted was assessed in vitro for responses stimulated by TNP-Ficoll. Under conditions in which TNP-Ficoll responses did not require T cells, it was observed that B cells from Fl yields greater than parent and fully allogeneic (A yields greater than B) radiation bone marrow chimeras were only triggered by macrophages expressing host H-2 determinants, and were not triggered by macrophages expresing donor H-2 determinants. This genetic restriction was not overcome by the addition of T cells. Indeed, it was observed that the activation of TNP-Ficoll responsive B cells by macrophages was genetically restricted requiring B cell recognition of macrohage H-2 determinants.